Natural biopolymers, such as proteins, frequently have ordered conformations, such as alpha-helix and beta-sheets, which contribute to the three-dimensional ordered structure and the specific function of the biopolymer. The structure of a protein is essential for the protein's function; it has been shown by many scientists that an unfolded protein may not be functional. More important, in the last few years there is increasing awareness of the danger of protein misfolding and misassembly into for example amyloid and other pathological forms. Misfolding can change a protein from something that is useful into nonfunctional, harmful or even toxic. Human health relies on properly folded protein, and in vivo deposition of amyloid fibrils is associated with many diseases related to protein conformation, including Alzheimer's disease (AD), Huntington's disease, (HD), Amyotrophic Lateral Sclerosis (ALS), systemic amyloidoses, and the prion diseases. The prion diseases, i.e. transmissible spongiform encephalopathy (TSE), in animals [e.g. bovine spongiform encephalopathy (BSE), Scrapie and chronic wasting disease (CWD)] and in humans [Creutzfeldt Jakob disease (CJD), Gerstmann-Strä ussler-Scheinker disease (GSS), Kuru] are associated with the conformational conversion of the normal cellular prion protein, (PrPC), to an infectious pathogenic disease-associated isoform denoted PrPSc. Proteins frequently alter their conformation due to different external stimuli and the importance of conformational changes of proteins leading to pathogenic states has been well documented. Especially under conditions that destabilize the native state, proteins can aggregate into characteristic fibrillar assemblies, known as amyloid fibrils. These beta-sheet rich protein assemblies have distinctively different conformations compared to that of the native state. The misfolded prion protein is even self-propagating (infectious), a property which is entirely encoded within the misfolded conformation.
Chronic human diseases seriously affect the healthcare system. It is well recognized that rapid and accurate diagnostic tools are necessary to afford early intervention and therapy. Only symptomatic therapy is available, like in Alzheimer's disease for example, and these have limited therapeutic efficacy. Presently there are no antemortem molecular diagnostic tests of Alzheimer's disease or transmissible spongiform encephalopathies (TSEs), and the clinical diagnostics that are performed require that disease progression is severe. Further, there are no efficient treatments available yet, and immunotherapy in for example Alzheimer's disease holds great promise. The lack of reliable methods to capture misfolded proteins, monitoring both treatment and disease progression is however a severe shortcoming in treatment of most protein misfolding related diseases.
The affinity between misfolded proteins in amyloid plaques, amyloid fibrils and amyloid like fibrils, and conjugated molecules compromised of repeating units of thiophene, ethylenedioxythiophene (EDOT), benzothiadizole, fluorene, and phenyl in homo and hetero oligomers and polymers with ionic or polar sidechains has been demonstrated in several in vitro studies. The interaction between amyloid like fibrils of insulin and anionic, zwitterionic and cationic poly- and oligo thiophenes was shown by [WO2005/109005]. Several of the mentioned oligomers and polymers have been shown to bind to amyloid, aβ and PrP deposits in histological sections [WO2007/091973]. Thiophene compounds have been suggested in therapy [WO2010/044743]. An anionic, more specifically an alkoxysulfonate derivative, polymer of EDOT showed high affinity for amyloid like fibrils [Hamedi, M. et al.;. Nano Lett.; (2008); 8,1736-1740]. Moreover a substituted polyfluorene and an alternating polyfluorene with a polyethylene oxide were demonstrated to strongly associate with amyloid like fibrils in vitro [Tanaka, H. et al.; Nano Lett.; (2008) 8,2858-2861].